Hydrolysis and depletion of phosphatidylglycerol at peak murine acute lung injury

Anionic phospholipids are essential for surfactant function and phosphatidylglycerol (PG) is the most abundant. Increased secretory phospholipase A2 (sPLA 2 ) and disproportionate depletion of PG is consistently observed in patients with acute respiratory distress syndrome (ARDS), leading to speculation on their potential relationship. We hypothesized that a non-lethal murine model of acute lung injury (ALI) would demonstrate a temporal association between lung inflammation, surfactant dysfunction, PG depletion, and sPLA 2 activity at peak ALI. ALI was induced in BALB/c mice by intratracheal lipopolysaccharide (IT-LPS). Markers of ALI, surfactant (function, recovery, and composition), and sPLA 2 activity were assessed over a 240-h period encompassing peak ALI and resolution. During peak ALI, a separate cohort of IT-LPS mice received IT-varespladib, an sPLA 2 inhibitor, with surfactant outcomes analyzed 4 h later. IT-LPS induced features of ALI, including immune cell influx, protein leak, histological injury, and respiratory dysfunction, which peaked at 48–96 h and resolved by 240 h. Impaired surfactant function at peak ALI was associated with increased sPLA 2 -mediated PG hydrolysis and reduced PG content. All changes were absent post-ALI resolution. Varespladib reduced alveolar sPLA 2 activity, increased surfactant PG, and improved surfactant function compared to untreated LPS controls. At peak ALI after IT-LPS, depletion of PG is synchronously related to surfactant dysfunction and increased sPLA 2 hydrolysis. Pharmacologic inhibition of sPLA 2 at peak ALI improves PG content and surfactant function. Additional substudies to fully examine their relationships and mechanisms are warranted.